CN113072448B - Aryl gemfibrozil derivative high-valence iodine compound and preparation method thereof - Google Patents
Aryl gemfibrozil derivative high-valence iodine compound and preparation method thereof Download PDFInfo
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- CN113072448B CN113072448B CN202110345557.9A CN202110345557A CN113072448B CN 113072448 B CN113072448 B CN 113072448B CN 202110345557 A CN202110345557 A CN 202110345557A CN 113072448 B CN113072448 B CN 113072448B
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- Prior art keywords
- gemfibrozil
- aryl
- derivative
- preparation
- iodine
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- -1 Aryl gemfibrozil derivative Chemical class 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 150000002497 iodine compounds Chemical class 0.000 title claims abstract description 25
- HEMJJKBWTPKOJG-UHFFFAOYSA-N Gemfibrozil Chemical compound CC1=CC=C(C)C(OCCCC(C)(C)C(O)=O)=C1 HEMJJKBWTPKOJG-UHFFFAOYSA-N 0.000 claims abstract description 53
- 125000003118 aryl group Chemical group 0.000 claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 12
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 42
- 229910052740 iodine Inorganic materials 0.000 claims description 42
- 239000011630 iodine Chemical group 0.000 claims description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 16
- LRIUKPUCKCECPT-UHFFFAOYSA-N [hydroxy(phenyl)-$l^{3}-iodanyl] 4-methylbenzenesulfonate Chemical class C1=CC(C)=CC=C1S(=O)(=O)OI(O)C1=CC=CC=C1 LRIUKPUCKCECPT-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 229910021332 silicide Inorganic materials 0.000 claims description 5
- FVBUAEGBCNSCDD-UHFFFAOYSA-N silicide(4-) Chemical compound [Si-4] FVBUAEGBCNSCDD-UHFFFAOYSA-N 0.000 claims description 5
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 claims description 5
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- AJDIZQLSFPQPEY-UHFFFAOYSA-N 1,1,2-Trichlorotrifluoroethane Chemical compound FC(F)(Cl)C(F)(Cl)Cl AJDIZQLSFPQPEY-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims 1
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Substances C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims 1
- 229960003627 gemfibrozil Drugs 0.000 abstract description 42
- 239000003814 drug Substances 0.000 abstract description 19
- 229940079593 drug Drugs 0.000 abstract description 18
- 238000010534 nucleophilic substitution reaction Methods 0.000 abstract description 5
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 31
- YKCQSETYDHFYFZ-UHFFFAOYSA-N methyl 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoate Chemical compound COC(=O)C(C)(C)CCCOC1=CC(C)=CC=C1C YKCQSETYDHFYFZ-UHFFFAOYSA-N 0.000 description 30
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 25
- 238000005481 NMR spectroscopy Methods 0.000 description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 17
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 14
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 8
- OIRDBPQYVWXNSJ-UHFFFAOYSA-N methyl trifluoromethansulfonate Chemical compound COS(=O)(=O)C(F)(F)F OIRDBPQYVWXNSJ-UHFFFAOYSA-N 0.000 description 8
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 229940050176 methyl chloride Drugs 0.000 description 7
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 7
- 238000001228 spectrum Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 230000009471 action Effects 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 6
- 238000012512 characterization method Methods 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 4
- LPNBBFKOUUSUDB-UHFFFAOYSA-M p-toluate Chemical compound CC1=CC=C(C([O-])=O)C=C1 LPNBBFKOUUSUDB-UHFFFAOYSA-M 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000012434 nucleophilic reagent Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 125000003107 substituted aryl group Chemical group 0.000 description 3
- FSXLZUKMPRDBFO-UHFFFAOYSA-N (2-hydroxy-6-iodophenyl) 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OC1=C(O)C=CC=C1I FSXLZUKMPRDBFO-UHFFFAOYSA-N 0.000 description 2
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 2
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- QZRGKCOWNLSUDK-UHFFFAOYSA-N Iodochlorine Chemical compound ICl QZRGKCOWNLSUDK-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 208000029078 coronary artery disease Diseases 0.000 description 2
- 238000001212 derivatisation Methods 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- LPNBBFKOUUSUDB-UHFFFAOYSA-N p-toluic acid Chemical compound CC1=CC=C(C(O)=O)C=C1 LPNBBFKOUUSUDB-UHFFFAOYSA-N 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- SYSZENVIJHPFNL-UHFFFAOYSA-N (alpha-D-mannosyl)7-beta-D-mannosyl-diacetylchitobiosyl-L-asparagine, isoform B (protein) Chemical compound COC1=CC=C(I)C=C1 SYSZENVIJHPFNL-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical group ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 1
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical group CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- FJMFQXYKHUJIAV-UHFFFAOYSA-N C1=CC(C)=CC=C1S(=O)(=O)OC1=C(I)C=CC(C)=C1O Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OC1=C(I)C=CC(C)=C1O FJMFQXYKHUJIAV-UHFFFAOYSA-N 0.000 description 1
- WLSHIUKTSLTWMC-UHFFFAOYSA-N CC(C=C1)=CC=C1S(OC1=C(C)C=C(C)C(O)=C1C)(=O)=O Chemical group CC(C=C1)=CC=C1S(OC1=C(C)C=C(C)C(O)=C1C)(=O)=O WLSHIUKTSLTWMC-UHFFFAOYSA-N 0.000 description 1
- XDEWNEJGNYUDPN-UHFFFAOYSA-N CC(O)=O.CC(O)=O.COC1=CC=C(I)C=C1 Chemical compound CC(O)=O.CC(O)=O.COC1=CC=C(I)C=C1 XDEWNEJGNYUDPN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 229910021594 Copper(II) fluoride Inorganic materials 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 238000010499 C–H functionalization reaction Methods 0.000 description 1
- 201000001376 Familial Combined Hyperlipidemia Diseases 0.000 description 1
- 102100030431 Fatty acid-binding protein, adipocyte Human genes 0.000 description 1
- 101710118908 Fatty acid-binding protein, adipocyte Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- VOTLAPGXCLKBHG-UHFFFAOYSA-N OC1=C(C(=C(C=C1)I)C1=C(C=C(C=C1C)C)C)OS(=O)(=O)C1=CC=C(C)C=C1 Chemical compound OC1=C(C(=C(C=C1)I)C1=C(C=C(C=C1C)C)C)OS(=O)(=O)C1=CC=C(C)C=C1 VOTLAPGXCLKBHG-UHFFFAOYSA-N 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 206010045263 Type IIb hyperlipidaemia Diseases 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- JHRWWRDRBPCWTF-OLQVQODUSA-N captafol Chemical group C1C=CC[C@H]2C(=O)N(SC(Cl)(Cl)C(Cl)Cl)C(=O)[C@H]21 JHRWWRDRBPCWTF-OLQVQODUSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- GWFAVIIMQDUCRA-UHFFFAOYSA-L copper(ii) fluoride Chemical compound [F-].[F-].[Cu+2] GWFAVIIMQDUCRA-UHFFFAOYSA-L 0.000 description 1
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 208000020346 hyperlipoproteinemia Diseases 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- JCZSQOVZJXDMTK-UHFFFAOYSA-N iodo trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)OI JCZSQOVZJXDMTK-UHFFFAOYSA-N 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 1
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- QSSJZLPUHJDYKF-UHFFFAOYSA-N methyl 4-methylbenzoate Chemical compound COC(=O)C1=CC=C(C)C=C1 QSSJZLPUHJDYKF-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- UYCAUPASBSROMS-AWQJXPNKSA-M sodium;2,2,2-trifluoroacetate Chemical compound [Na+].[O-][13C](=O)[13C](F)(F)F UYCAUPASBSROMS-AWQJXPNKSA-M 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
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Abstract
The invention discloses a high-valence iodine compound of an aryl gemfibrozil derivative and a preparation method thereof. The aryl gemfibrozil derivative hypervalent iodine compound has a structural formula (I), is a high-efficiency electrophilic reagent, and can realize nucleophilic substitution reaction of a specific site on the aryl of gemfibrozil molecules, so that the aims of modifying the gemfibrozil drug molecules and expanding the species of the gemfibrozil drug molecules are fulfilled. Meanwhile, the invention provides a preparation method of the compound, and the method is direct, simple and efficient, and is suitable for preparing aryl gemfibrozil derivative high-valence iodine compounds in a large scale.
Description
Technical Field
The invention belongs to the technical field of organic synthetic chemistry, and particularly relates to an aryl gemfibrozil derivative high-valence iodine compound and a preparation method thereof.
Background
Gefilosin belongs to a chlorine Bei Dingsuan derivative and is a commonly used lipid-lowering drug in clinic. The pharmacological actions mainly comprise the protection action of myocardial ischemia reperfusion injury, the action of resisting hepatic cell fatty lesion, the action of reducing FFA and AFABP, the action of reducing blood sugar and the action of relaxing aorta. Can be used for treating severe IV or V type hyperlipoproteinemia, coronary heart disease, and patients with high risk and ineffective diet control and weight loss; it is also used for treating type IIb hyperlipoproteinemia, coronary heart disease, high risk, diet control, weight loss, and other blood lipid regulating medicines. Therefore, the field of synthesis of the compounds needs to develop an efficient, simple and economical method.
So far, the modification on the gemfibrozil aryl is realized by modifying the aliphatic chain hydrocarbon carboxyl of the gemfibrozil or directly performing C-H activation on the gemfibrozil aryl, but the method usually needs to use a transition metal catalyst, has poor selectivity and has narrow application range. The gemfibrozil drug molecules obtained by the above reported reactions are very limited, and are not beneficial to constructing a huge gemfibrozil drug library. Therefore, an effective method with simple preparation process, good selectivity and wide application range is lacked for synthesizing the gemfibrozil derivatives.
Disclosure of Invention
The invention aims to provide a high-valence iodine compound of an aryl gemfibrozil derivative and a preparation method thereof aiming at the defects of the prior art. The aryl gemfibrozil derivative high-valence iodine compound can be used for synthesizing various aryl-substituted gemfibrozil drug molecules through a nucleophilic substitution reaction with a nucleophilic reagent, and further promotes the discovery process of active leads of the gemfibrozil drugs.
In order to realize the purpose, the technical scheme adopted by the invention is as follows: an aryl gemfibrozil derivative hypervalent iodine compound, the structure of which is shown as the formula (I):
(I)
in the formula (I), X is one of halogen, hydroxyl, acetoxy, tetrafluoroborate, sulfonic group, methanesulfonic group, trifluoromethanesulfonic group, benzenesulfonic group, p-toluenesulfonic group, hexafluorophosphoric acid group, bistrifluoromethyl and sulfonimide group;
ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, and H on the aryl or the heteroaryl is independently substituted by halogen, saturated alkyl, substituted alkyl, aryl, substituted aryl, acyl, nitro, trifluoromethyl or alkoxy;
r is alkyl or aryl;
the halogen is selected from fluorine, chlorine, bromine or iodine.
The aryl gemfibrozil derivative high-valence iodine compound is a high-efficiency electrophilic reagent, and can realize nucleophilic substitution reaction of a specific site on the aryl of the gemfibrozil molecules, so that the aims of modifying the gemfibrozil drug molecules and expanding the species of the gemfibrozil drug molecules are fulfilled.
As a preferred embodiment of the present invention, ar comprises the following groups:
said R is 1 、R 2 、R 3 、R 4 And R 5 The groups are the same or different and are respectively and independently selected from halogen, saturated alkyl, substituted alkyl, aryl, substituted aryl, acyl, nitro, trifluoromethyl and alkoxy.
As a preferred embodiment of the present invention, the compound represented by the formula (1) includes the following compounds:
the invention also claims a preparation method of the aryl gemfibrozil derivative hypervalent iodine compound, which comprises the following steps:
mixing Koser's reagent derivatives or aryl iododiacetic acid compounds with halogenated solvents and gemfibrozil derivatives uniformly at room temperature, cooling the mixed solution to-5~4 ℃, adding trimethyl silicide at 5-40 ℃ and reacting for 0.5-1.5 hours to obtain the aryl gemfibrozil derivative high-valence iodine compounds.
As a preferred embodiment of the present invention, the Koser's reagent derivative has a structural formula shown in formula (1):
(1)
as a preferred embodiment of the present invention, the structural formula of the aryl iododiacetic acid compound is represented by formula (2):
(2)
as a preferred embodiment of the present invention, the gemfibrozil derivative has the structure shown in formula (II):
(II)
the invention carries out anion ligand exchange reaction on gemfibrozil derivatives and Koser's reagent derivatives or aryl iododiacetic acid compounds to prepare aryl gemfibrozil derivative hypervalent iodine compounds, and the synthetic route is as follows:
as a preferred embodiment of the present invention, the trimethylsilicand is one of trimethylsilicand chloride, trimethylsilicand bromide, trimethylsilicand iodide, trimethylsilicane acetic acid, sodium trifluoroacetate trimethylsilicane, trimethylsilicane methanesulfonate, trimethylsilicane trifluoromethanesulfonate, trimethylsilicane benzenesulfonate; the molar ratio of the Koser's reagent derivative to the gemfibrozil derivative is 0.8-1.2: 0.8-1.2; the ratio of the Koser's reagent derivative to the halogenated solvent is 1 to 2mmol:2 to 5mL; the molar ratio of the trimethyl silicide to the gemfibrozil derivative is 0.8 to 1.2: 0.8 to 1.2.
As a preferred embodiment of the invention, the halogenated solvent is at least one of dichloromethane, chloroform, 1,1,2-trifluorotrichloroethane, carbon tetrachloride, hexafluoroisopropanol, 2,2,2-trifluoroethanol, and dichloroethylene.
As a preferable embodiment of the method for preparing the aryl gemfibrozil derivative hypervalent iodine compounds according to the invention, the reaction solution is reacted at room temperature for 0.5 to 24 hours, then the solvent is distilled off under reduced pressure, and a weakly polar solvent is added to obtain the aryl gemfibrozil derivative hypervalent iodine compounds; the weak polar solvent is at least one of diethyl ether, n-hexane and petroleum ether.
The invention claims the application of aryl gemfibrozil derivative hypervalent iodine compounds in preparing aromatic ring modified gemfibrozil derivative medicines.
The invention also claims a derivatization method for aromatic ring modification of gemfibrozil derivatives, which is characterized in that aryl gemfibrozil derivative hypervalent iodine compounds as described in claim 1 are reacted with nucleophilic reagent in solvent to produce gemfibrozil derivative drugs modified by aromatic rings; the solvent is at least one of dimethylformamide, toluene, dichloroethane, dichloromethane, chloroform, tetrahydrofuran, dioxane, benzene, toluene, trifluorotoluene, acetonitrile, ethyl acetate, diethyl ether, methyl tert-butyl ether, n-hexane, cyclohexane and petroleum ether.
In addition, the invention also claims a gemfibrozil derivative drug modified by an aromatic ring, which is prepared by a derivatization method modified by the aromatic ring of the gemfibrozil derivative; the aromatic ring modified gemfibrozil derivative has a drug structure shown in formula (III):
(III)
nu is a nucleophilic group, and the nucleophilic group at least contains one nitrogen atom, one oxygen atom, one phosphorus atom, one sulfur atom and one fluorine atom.
The aryl gemfibrozil derivative hypervalent iodine compound is a high-efficiency electrophilic reagent, can realize nucleophilic substitution reaction of a specific site on the aryl of a gemfibrozil molecule with a nucleophilic reagent, and the synthetic route of the aromatic ring modified gemfibrozil derivative medicine molecule is as follows:
compared with the prior art, the invention has the following beneficial effects: the aryl gemfibrozil derivative high-valence iodine compound is a high-efficiency electrophilic reagent, and can realize nucleophilic substitution reaction of a specific site on the aryl of gemfibrozil molecules, so that the aim of modifying the drug molecules is fulfilled, the types of the drug molecules are expanded, and meanwhile, the preparation method of the compound is provided. The method can directly, simply, efficiently and massively prepare the aryl gemfibrozil derivative high-valence iodine compound. The compound is easy to prepare, stable and high in reaction activity, the high-valence iodine compound can be used for carrying out simple and clear structural modification on gemfibrozil molecules, the structural diversity and the rapid synthesis of the drug molecules are realized, a large drug compound library is convenient to construct rapidly, and the discovery process of a drug active precursor is greatly promoted.
Drawings
FIG. 1 shows the preparation of phenyl gemfibrozil methyl ester triflate higher iodine prepared according to example 1 of the present invention 1 H NMR spectrum;
FIG. 2 shows the preparation of phenyl gemfibrozil methyl ester triflate higher iodine prepared according to example 1 of the present invention 13 A C NMR spectrum;
FIG. 3 shows the preparation of higher iodine 4-methylphenyl gemfibrozil methyl triflate prepared according to example 2 of the present invention 1 H NMR spectrum;
FIG. 4 shows the preparation of higher iodine 4-methylphenyl gemfibrozil methyl triflate prepared according to example 2 of the present invention 13 A C NMR spectrum;
FIG. 5 shows the preparation of 2,4,6-trimethylphenyl gemfibrozil methyl ester triflate higher iodine prepared in example 3 of the present invention 1 H NMR spectrum;
FIG. 6 shows the preparation of 2,4,6-trimethylphenyl gemfibrozil methyl ester triflate higher iodine prepared in example 3 of the present invention 13 A C NMR spectrum;
FIG. 7 shows the preparation of 4-methoxyphenyl gemfibrozil methyl ester with higher iodine chloride value prepared in example 4 of the present invention 1 H NMR spectrum;
FIG. 8 shows the preparation of 4-methoxyphenyl gemfibrozil methyl ester with higher iodine chloride value prepared in example 4 of the present invention 13 A C NMR spectrum;
FIG. 9 shows the preparation of higher iodine phenyl gemfibrozil triflate according to the invention in example 5 1 H NMR spectrum;
FIG. 10 shows the higher iodine content of phenyl gemfibrozil triflate prepared in example 5 of the present inventionIs/are as follows 13 A C NMR spectrum;
FIG. 11 is a graph of gemfibrozil methyl fluoride prepared in example 6 of the present invention 1 H NMR spectrum;
FIG. 12 is a graphic representation of gemfibrozil methyl ester fluoride, prepared in example 6 of the invention 13 A C NMR spectrum;
FIG. 13 is a graphic representation of gemfibrozil methyl ester fluoride, prepared in example 6 of the invention 19 F, atlas;
FIG. 14 shows the preparation of gemfibrozil methyl ester p-toluate according to example 7 of the present invention 1 H NMR;
FIG. 15 is a graphic representation of gemfibrozil methyl ester p-toluate prepared in example 7 of the present invention 13 C NMR spectrum.
Detailed Description
To better illustrate the objects, technical solutions and advantages of the present invention, the present invention will be further described with reference to specific examples.
Example 1
The preparation of phenyl gemfibrozil methyl ester triflate higher iodine described in this example comprises the following steps:
(1) In a 100 mL round bottom flask, 10 mmol of hydroxy (p-toluenesulfonyloxy) iodobenzene was added to a mixed solution of 30 mL dichloromethane and 5mL of 2, 2-trifluoroethanol, followed by addition of 10 mmol of gemfibrozil methyl ester compound, followed by dropwise addition of 10 mmol of trimethylsilyl trifluoromethanesulfonate, followed by reaction at room temperature of 1h;
(2) After the reaction is finished, the solvent is removed by reduced pressure distillation, 70 mL ethyl ether is added for precipitation, and white solid phenyl gemfibrozil methyl ester trifluoromethanesulfonate high-valence iodine is obtained, wherein the yield is 83%.
FIG. 1 shows the preparation of phenyl gemfibrozil methyl ester triflate higher iodine prepared according to example 1 of the present invention 1 H NMR, FIG. 2 is a graphic representation of higher iodine phenyl gemfibrozil methyl ester triflate prepared according to example 1 of the present invention 13 C NMR spectrum. As can be seen from the nuclear magnetic spectra of fig. 1 and fig. 2, the nuclear magnetic characterization peaks of the iodine valence of phenyl gemfibrozil methyl triflate are as follows: 1 H NMR (400 MHz, CDCl 3 ): δ 7.80 (d, J = 5.9 Hz, 3H), 7.52 (t, J = 7.4 Hz, 1H), 7.40 (t, J = 7.8 Hz, 2H), 6.81 (s, 1H), 3.94 (t, J = 5.7 Hz, 2H), 3.64 (s, 3H), 2.52 (s, 3H), 2.17 (s, 3H), 1.77 – 1.63 (m, 4H), 1.20 (s, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 7.81, 7.79, 7.54, 7.52, 7.51, 7.42, 7.40, 7.38, 6.81, 3.95, 3.94, 3.93, 3.64, 2.52, 2.17, 1.73, 1.72, 1.72, 1.69, 1.68, 1.66, 1.20. The invention example 1 is shown to successfully prepare phenyl gemfibrozil methyl ester triflate high-valence iodine.
The structural formula of phenyl gemfibrozil methyl ester triflate high-valence iodine is as follows:
example 2
The preparation of 4-methylphenyl gemfibrozil methyl triflate higher iodine described in this example comprises the following steps:
(1) Dissolving 10 mmol of 4-methyliodibenzene in 40 mL dichloromethane in a 100 mL round-bottom flask, adding 10 mmol of m-chloroperoxybenzoic acid under stirring, then adding 10 mmol of p-toluenesulfonic acid monohydrate, stirring at room temperature for 1h, after the reaction is completed, spin-drying the solvent, adding 70 mL ethyl ether, stirring fully for 30 min to generate a precipitate, filtering, and drying in vacuum to obtain hydroxyl (p-toluenesulfonyloxy) 4-methyliodibenzene with the yield of 98%;
(2) In a 100 mL round bottom flask, 8 mmol of hydroxy (p-toluenesulfonyloxy) 4-methyliodobenzene from step (1) was added to a mixed solution of 25 mL dichloromethane and 4 mL of 2, 2-trifluoroethanol, followed by addition of 8 mmol of gemfibrozil methyl ester compound, followed by dropwise addition of 8 mmol of trimethylsilyl trifluoromethanesulfonate, followed by reaction at room temperature for 1h;
(3) And (3) after the reaction in the step (2) is finished, distilling under reduced pressure to remove the solvent, adding 70 mL diethyl ether for precipitation to obtain white solid 4-methylphenyl gemfibrozil methyl ester high-valence iodine trifluoromethanesulfonate, wherein the total yield is 79%.
FIG. 3 is the 4-methylphenyl gemfibrozil methyl ester trifluoromethyl ester prepared in example 2 of the inventionSulfonic acid high valence iodine 1 H NMR spectrum, FIG. 4 is a higher iodine value of 4-methylphenyl gemfibrozil methyl triflate prepared in example 2 of the present invention 13 C NMR spectrum, and as can be seen from the nuclear magnetic spectra of FIGS. 3 and 4, the nuclear magnetic characterization peak of the high-valence iodine of 4-methylphenyl gemfibrozil methyl ester triflate is as follows: 1 H NMR (400 MHz, CDCl 3 ): δ 7.78 (s, 1H), 7.69 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 6.79 (s, 1H), 3.95 (t, J = 5.9 Hz, 2H), 3.65 (s, 3H), 2.54 (s, 3H), 2.37 (s, 3H), 2.18 (s, 3H), 1.77 – 1.65 (m, 4H), 1.21 (s, 6H); 13 C NMR (101 MHz, CDCl 3 ) δ 178.25, 161.27, 143.19, 141.37, 138.99, 133.83, 133.12, 129.55, 113.91, 109.40, 105.66, 68.61, 51.93, 42.16, 36.95, 25.79, 25.29, 24.96, 21.42, 15.72. The invention example 2 is shown to successfully prepare the high-valence iodine 4-methyl phenyl gemfibrozil methyl triflate.
The structural formula of the 4-methyl phenyl gemfibrozil methyl triflate high-valence iodine is as follows:
example 3
This example, which describes 2,4,6-trimethylphenyl gemfibrozil methyl ester triflate, provides a process for the preparation of higher iodine comprising the steps of:
(1) Dissolving 10 mmol of iodine in 100 mL dichloromethane in a round-bottom flask of 250 mL, adding 20 mmol of mesitylene under stirring, then adding 30 mmol of m-chloroperoxybenzoic acid and 20 mmol of p-toluenesulfonic acid monohydrate, reacting at room temperature for 1 hour, after the reaction is finished, spin-drying the solvent, adding 150 mL ethyl ether, stirring fully for 30 minutes to generate a precipitate, filtering, and drying in vacuum to obtain hydroxyl (p-toluenesulfonyloxy) mesitylene with the yield of 97 percent;
(2) In a 100 mL round bottom flask, 8 mmol of hydroxy (p-toluenesulfonyloxy) mesityliodobenzene obtained in step (1) was added to a mixed solution of 25 mL dichloromethane and 3 mL of 2, 2-trifluoroethanol, followed by addition of 8 mmol of gemfibrozil methyl ester compound, followed by dropwise addition of 8 mmol of trimethylsilyl trifluoromethanesulfonate, followed by reaction at room temperature for 1 hour;
(3) And (3) after the reaction in the step (2) is finished, removing the solvent by reduced pressure distillation, adding 70 mL diethyl ether for precipitation to obtain a white solid 2,4,6-trimethylphenyl gemfibrozil methyl ester trifluoromethanesulfonate high-valence iodine with the total yield of 54%.
FIG. 5 shows 2,4,6-trimethylphenyl gemfibrozil methyl ester triflate hypervalent iodine prepared in example 3 of the invention 1 H NMR spectrum, FIG. 6 is a 2,4,6-trimethylphenyl gemfibrozil methyl ester triflate higher iodine prepared in example 3 of the present invention 13 C NMR spectrum, and nuclear magnetic characterization peaks of 2,4,6-trimethylphenyl gemfibrozil methyl ester triflate higher iodine can be seen from the nuclear magnetic spectra of FIGS. 5 and 6: 1 H NMR (400 MHz, CDCl 3 ): δ 7.35 (s, 1H), 7.07 (s, 2H), 6.76 (s, 1H), 3.93 (t, J = 5.9 Hz, 2H), 3.65 (s, 3H), 2.61 (s, 6H), 2.51 (s, 3H), 2.34 (s, 3H), 2.12 (s, 3H), 1.76 – 1.65 (m, 4H), 1.21 (s, 6H); 13 C NMR (101 MHz, CDCl 3 ) δ 178.23, 160.63, 144.22, 142.29, 140.36, 136.70, 130.70, 129.54, 119.84, 114.23, 103.38, 68.62, 51.92, 42.15, 36.95, 26.97, 25.28, 24.95, 21.13, 15.91. The invention example 3 shows that 2,4,6-trimethylphenyl gemfibrozil methyl ester trifluoro methanesulfonic acid high valence iodine is successfully prepared.
2,4,6-Trimethylphenylgemfibrozil methyl triflate hypervalent iodine has the structural formula:
example 4
The preparation of 4-methoxyphenyl gemfibrozil methyl chloride higher iodine described in this example comprises the following steps:
(1) Adding 10 mmol of p-iodoanisole, 11 mmol of sodium periodate, 20 mmol of sodium acetate, 15 mL acetic acid and 1.5 mL acetic anhydride into a 100 mL sealed tube, heating to 120 ℃, reacting for 3 hours, adding water after the reaction is finished, adding dichloromethane for extraction for three times, collecting an organic phase, drying by anhydrous sodium sulfate, decompressing and spin-drying to obtain an oily substance, finally adding n-hexane into the oily substance, performing ultrasonic treatment for 30 minutes, and filtering to obtain the iodine-p-methoxybenzene diacetate with the yield of 92%;
(2) Adding 30 mL hexafluoroisopropanol and 8.5 mmol gemfibrozil methyl ester into a 100 mL round-bottom flask, then adding 8.5 mmol iodop-methoxybenzene diacetate, cooling to 0 ℃, adding 8.5 mmol trimethylchlorosilane dropwise with stirring, and reacting 1h at room temperature;
(3) After the reaction is finished, the solvent is distilled and suspended under reduced pressure, and diethyl ether is added for precipitation to obtain pink solid 4-methoxyphenyl gemfibrozil methyl chloride high-valence iodine compound with the total yield of 59 percent.
FIGS. 7 and 8 are schematic views showing the preparation of 4-methoxyphenyl gemfibrozil methyl ester chloride higher iodine according to example 4 of the present invention 1 H NMR and 13 c NMR spectrum, and as can be seen from the nuclear magnetic spectra of FIGS. 7 and 8, the nuclear magnetic characterization peak of the high-valence iodine of 4-methoxyphenyl gemfibrozil methyl chloride is as follows: 1 H NMR (400 MHz, CDCl 3 ):δ 7.76 (s, 1H), 7.75 (d, J = 3.2 Hz, 2H), 6.80 (d, J = 9.0 Hz, 2H), 6.70 (s, 1H), 3.90 (t, J = 5.7 Hz, 2H), 3.75 (s, 3H), 3.64 (s, 3H), 2.56 (s, 3H), 2.13 (s, 3H), 1.72 – 1.63 (m, 4H), 1.19 (s, 6H). 13 C NMR (101 MHz, CDCl 3 ) δ 178.25, 162.75, 161.19, 141.13, 138.71, 136.14, 129.53, 118.08, 113.86, 106.35, 101.51, 68.61, 55.84, 51.93, 42.16, 36.96, 25.74, 25.30, 24.97, 15.73. The invention example 4 is shown to successfully prepare the 4-methoxyphenyl gemfibrozil methyl chloride high-valence iodine.
The structural formula of the 4-methoxyphenyl gemfibrozil methyl chloride higher iodine is as follows:
example 5
The preparation of higher iodine phenyl gemfibrozil triflate described in this example comprises the following steps:
(1) In a 100 mL round bottom flask, 10 mmol of hydroxy (p-toluenesulfonyloxy) iodobenzene was added to a mixed solution of 30 mL dichloromethane and 5mL of 2, 2-trifluoroethanol, followed by 10 mmol of gemfibrozil, followed by dropwise addition of 10 mmol of trimethylsilyl trifluoromethanesulfonate, followed by reaction of 1h at room temperature;
(2) After the reaction is finished, the solvent is removed by reduced pressure distillation, 70 mL ethyl ether is added for precipitation, and white solid phenyl gemfibrozil triflate high-valence iodine is obtained, wherein the yield is 89%.
FIGS. 9 and 10 are respectively a graphic representation of the higher iodine phenyl gemfibrozil triflate prepared in example 5 of the present invention 1 H NMR and 13 c NMR spectrum, as can be seen from the nuclear magnetic spectra of FIGS. 9 and 10, the nuclear magnetic characteristic peak of the high-valence iodine of phenyl gemfibrozil triflate is: 1 H NMR (400 MHz,DMSO-d6): δ 8.18 – 8.08 (m, 3H), 7.63 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.7 Hz, 2H), 7.10 (s, 1H), 3.99 (t, J = 5.4 Hz, 2H), 2.55 (s, 3H), 2.13 (s, 3H), 1.70 – 1.53 (m, 4H), 1.10 (s, 6H); 13 c NMR (101 MHz, DMSO-d 6) delta 178.70, 159.89, 140.48, 138.33, 134.66, 131.76, 127.42, 122.34, 116.01, 113.87, 109.27, 68.30, 41.02, 36.34, 24.94, 24.50, 15.16. The invention example 5 shows that phenyl gemfibrozil triflate higher iodine is successfully prepared.
The structural formula of phenyl gemfibrozil methyl ester triflate high-valence iodine is as follows:
example 6
The preparation of gemfibrozil methyl ester fluoride as described in this example comprises the following steps:
in a 25 mL sealed tube, 0.4 mmol copper difluoride, 0.1 mmol copper trifluoromethanesulfonate, 0.1 mmol 18-crown ether-6 and 0.2 mmol 4-methoxyphenyl gemfibrozil methyl chloride are added under the protection of nitrogen and stirred, 2 mL dried dimethylformamide is added to react at 85 ℃ for 10 h, saturated potassium bicarbonate aqueous solution is used for treatment after the reaction is finished, dichloromethane is added, an organic phase is washed for three times and dried by anhydrous sodium sulfate, and the mixture is separated and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 40: 1) to obtain colorless transparent liquid with the separation yield of 69%.
FIGS. 11, 12 and 13 are, respectively, gemfibrozil methyl ester fluoride, prepared in example 6 of the present invention 1 H NMR, 13 C NMR and 19 f NMR. As can be seen from the nuclear magnetic spectra of fig. 11, 12 and 13, the nuclear magnetic characterization peaks of gemfibrozil methyl ester fluoride: 1 H NMR (400 MHz, CDCl 3 ):δ 6.76 (d, J = 9.9 Hz, 1H), 6.54 (d, J = 6.5 Hz, 1H), 3.86 (t, J = 2.7 Hz, 2H), 3.65 (s, 3H), 2.20 (d, J = 1.3 Hz, 3H), 2.15 (s, 3H), 1.71 (dd, J = 7.1, 3.4 Hz, 4H), 1.21 (s, 6H); 13 C NMR (101 MHz, CDCl 3 ) δ 178.36, 156.39, 154.04, 152.87, 125.64, 121.81, 116.80, 113.87, 68.79, 51.82, 42.19, 37.20, 25.28, 15.86, 14.62.19F NMR (376 MHz, CDCl 3) δ -128.95 (s, 1F). Indicating the success of the present invention, example 9, in the preparation of gemfibrozil methyl fluoride.
Gemfibrozil methyl ester fluoride has the structural formula:
example 7
The preparation of the reaction for the p-toluate ester of gemfibrozil described in this example comprises the following steps:
adding 0.22 mmol of potassium tert-butoxide and 2 mL dried toluene in a 25 mL sealed tube under nitrogen atmosphere, keeping strong stirring, then adding 0.22 mmol of p-toluic acid and 0.2 mmol of 4-methoxyphenyl gemfibrozil methyl chloride high-valent iodine, reacting for 3h at 130 ℃, adding water after the reaction is finished, transferring into a separating funnel, extracting with dichloromethane, washing with saturated saline, collecting an organic phase, drying with anhydrous sodium sulfate, separating and purifying the reaction mixture by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 30: 1) to obtain colorless transparent liquid, wherein the separation yield is 77%.
FIGS. 14 and 15 are gemfibrozil methyl ester p-toluate, prepared for example 7 of the present invention 1 H NMR and 13 c NMR spectrum from the chartThe nuclear magnetic spectrum of 14 and 15 shows the nuclear magnetic characteristic peaks of the methyl p-toluate gemfibrozil: 1 H NMR (400 MHz, CDCl 3 ): 8.09 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 6.88 (s, 1H), 6.65 (s, 1H), 3.92 (t, J = 4.9 Hz, 2H), 3.67 (s, 3H), 2.44 (s, 3H), 2.19 (s, 3H), 2.15 (s, 3H), 1.72 (d, J = 2.8 Hz, 4H), 1.22 (s, 6H); 13 C NMR (101 MHz, CDCl 3 ) δ 178.41, 165.52, 154.87, 144.32, 142.41, 130.27, 129.37, 127.87, 127.01, 125.48, 123.92, 113.37, 68.49, 51.88, 42.21, 37.22, 25.32, 21.86, 16.38, 15.94. The present invention, example 7, shows the successful preparation of methyl ester p-toluate of gefitinib.
The structural formula of gemfibrozil methyl ester p-toluate is as follows:
although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the true spirit and scope of the present invention.
Claims (2)
1. A preparation method of aryl gemfibrozil derivative hypervalent iodine compounds is characterized in that the structure of the aryl gemfibrozil derivative hypervalent iodine compounds is shown as a formula (I):
(I)
in the formula (I), X is chlorine, bromine, iodine or trifluoromethanesulfonyl;
r is alkyl;
ar is selected fromWherein R is 1 、R 2 、R 3 、R 4 And R 5 Each independently selected from halogen, saturated alkyl, aryl, nitro, trifluoromethyl or alkoxy;
the preparation method comprises the following steps:
mixing Koser's reagent derivatives or aryl iododiacetic acid compounds with halogenated solvents and gemfibrozil derivatives uniformly at room temperature, cooling the mixed solution to-5~5 ℃, adding trimethyl silicide at 5 to 40 ℃ and reacting for 0.5 to 24 hours to obtain aryl gemfibrozil derivative high-valence iodine compounds;
the Koser's reagent derivative has a structural formula shown as a formula (1):
(1);
the structural formula of the aryl iododiacetic acid compound is shown as the formula (2):
(2);
the reaction formula is shown as follows:
The trimethyl silicide is one of TMSCl, TMSBr, TMSI and trimethylsilyl trifluoromethanesulfonate;
the halogenated solvent is at least one of dichloromethane, chloroform, 1,1,2-trifluorotrichloroethane, carbon tetrachloride, hexafluoroisopropanol and 2,2,2-trifluoroethanol.
2. The method of claim 1, wherein the molar ratio of Koser's reagent derivative to gemfibrozil derivative is 0.8 to 1.2: 0.8 to 1.2; the ratio of the Koser's reagent derivative to the halogenated solvent is 1 to 2mmol:2 to 5mL; the molar ratio of the trimethyl silicide to the gemfibrozil derivative is 0.8 to 1.2: 0.8 to 1.2.
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CN110857268A (en) * | 2018-08-23 | 2020-03-03 | 北京厚燊药德科技有限责任公司 | Phenoxy acid compound and medical application thereof |
CN111943874A (en) * | 2020-08-14 | 2020-11-17 | 五邑大学 | Aryl naproxen derivative high-valence iodine compound and preparation method and application thereof |
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CN111943874A (en) * | 2020-08-14 | 2020-11-17 | 五邑大学 | Aryl naproxen derivative high-valence iodine compound and preparation method and application thereof |
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